Novel bisacetamides



United States. Patent 3,135,792 NOVEL BISACETAMIDES William F. Bruce,Havertown, and Joseph Tokolics, King of Prussia, Pa., assignors toAmerican Home Products Corporation, New York, N.Y., a corporation ofDelaware No Drawing. Filed Mar. 6, 1962, Ser. No. 177,751

2 Claims. (Cl. 260558) The invention relates generally to amides, andmore particularly to novel bisacetamides and salts thereof.

In US. Patent 2,780,646 there are disclosed novel alkanolaminobisacetamides, their salts, and methods for producing them. Asnoted in the patent, the compounds disclosed and claimed therein showsurprisingly good cal anesthetic action. However, it is stated in thepatent that the replacement in the class of compounds disclosed therein,of the hydroxy group with an amino radical, for example, was found todestroy the local anesthetic action and that other than in the cases ofaliphatic, aromatic or heterocyclic or inorganic acid esters of saidcompounds, no prediction With regard to local anesthetic action ispossible when other radicals replace the alkanol residue attached to theamino nitrogen atom.

It has now been discovered that certain other bisacetamides as definedhereinafter which include compounds that do not contain an alkanolresidue also show good local anesthetic action and, in addition, alsoshow broad spectrum antibiotic action. The new compounds, in the form ofthe free bases, may be represented by the formula:

rrs-m-u Y-C-N phenylor substituted phenyl-lower alkyl radicals whereinsuch substituents as lower alkyl-, lower alkoxy-, hy-

droxy-, halogen-, nitro-, amino-, monoor di-lower alkyl- 1 aminoradicals may be on the ring. In the case of aralkyls of thebeta-phenylethyl type, hydroxy substituents on the beta-carbon of thealkyl are also contemplated. The lower-alkyl substituted ethylenescontemplated by the in vention include, for example, the groups and thelike. The hydroxy-lower-alkyl substituted ethylenes referred to areintended to include similar groups wherein the alkyl substituent orsubstituents may be replaced by hydroxy-alkyl radicals such as in andthe like. It has been discovered that when more than two carbon atomsseparate the sulfur atom from the nitrogen atom of the amino group, thedesired activity of the resulting compounds is affected adversely.However, increase of the total number of carbon atoms of the alkylenechain by the presence of branch chains does not have such effect norwhen hydroxy-alkyl groups supply the additional carbon atoms, asexemplified above.

' The combined local anesthetic action and antibiotic ac-.

' the classes specified above. For example the compounds (I) NH .CH .CHN.[CHCON (II) HO.(CH .N.[CH CON (CH .C (CH .CH .C H 2 were found to haveneither anesthetic nor substantial antibiotic action.

Compounds falling within the scope of the formula as given above may beused in the form of acid-addition salts while still retaining theireffectiveness for local anesthetic use or antibiotic action as the case.may be. The salts provide great flexibility in therapeutic use sincethey may impart Various degrees of Water-solubility to an otherwisesubstantially insoluble base. With reference to the acid-addition salts,either organic or inorganic acids may be used as long as they do notsubstantially increase toxicity of the compound, particularly when thecompound is to be used for its local anesthetic or in vivo antibioticfunction. Thus, the hydrochloride, sulfate,

phosphate, hydrobromide, acetate, tartrate, propionate.

or succinate are among the salts considered useful for the purposesindicated.

In preparing the novel bisacetamides of the invention,

the free bases are prepared by reacting an appropriate amine which willfurnish the desired mercapto-alkyleneamino residue (as defined above) inthe final compound, with an alpha-halo-fatty acid amide containing therequired lower alkyl and aralkyl substituents on the nitrogen atom asspecified hereinbefore, in a molar ratio of 1:2. Preferably, the amideis present in slight'excess of the ratios stated.

On the other hand, where the fatty acid amide residues in the finalcompounds are desired to be dissimilar, as,

for example, where X and Y are to be different alkylene radicals orwhere R is to differ from R the bases may I be prepared by initiallyreacting in a molar ratio of say about 1:1, the chosen amine that Willsupply the mercapto-alkylene-amino radical as defined herein, with ahalo-fatty acid amide that will supply the X and R radicals desired. Theresulting amino-fatty acid amide may then be reacted with anotherhalo-fatty acid amide in say about 1:1 molar ratio, thelatter amidebeing chosen so that it will supply the differing Y and R radicalsdesired in the final bisacetamide. Alternately, appropriate mixtures ofdiffering halo-fatty acid amides may be reacted simultaneously with theamine compound. The halogen atom in. the halo-fatty acid amides used maybe either chlorine or bromine." Generally, the bisacetamides of theinvention are prepared as taught by the general procedure outlined inthe patents to Bruce et a1., 2,568,142, dated September 18, 1951, or2,654,754, dated October 6, 1953, suitably modified, of course, toprovide the proper amine and halogenated reactants.

The reaction of the amide and amine is carried out substantially underconditions as described in the above sole, dioxane hydrocarbon solvents,such as xylene, or in Patented June 2, 1964- tors may be an alkali oralkaline earth metal oxide, carbonate or bicarbonate, pyridine, or likesubstances.

To prepare; the acid-addition salts of the compounds discussed herein,the free base is generally dissolved in a suitable solvent and theselected acid is added thereto. Such'preparation of acid-addition saltsis .well known and hence need not be described herein.

The following example illustrates the preparation of a typical compoundfalling withinthe scope of the invention. a a

V 4 rating would designate local anesthetic action persisting from -20hours. This scale is employed in the table below. a a

In testing for bacteriostatic action, the method generally comprisedpreparation of a plurality of Petri dishes each containing apredeterminedamount of agar media into which solutions of decreasinglyvarying concentrations of each of the compounds under consideration wereincorporated starting with a maximum concentration thereof per volume ofsolution, to which a standard volume of a given bacterial strainwaslater introduced. If bacterial growth was observed to be halted, thesame standard volumes of the given bacterial strain were separatelyadded to 'each of other agar specimens containing EXAMPLEI 15 lesseramounts of the compound beingtested. In said r decreasin concentrationsof a specified Preparatzon of 2,2 -(2-Mercapt0-Ethylzmmo)Bls [N-(a, agarspecimens k V a DimethylphenethyD- N Methylacetamide]Hydr0 g fis g of1000 m 10 and Wfire chlonde In the specific application utilized, aseriesof stock solutions were prepared, each at a level of 10,000 ig/ml,oH,-0- -o-()H,- by dissolving the compound being tested in water. As I HH l known in the art, other suitable solvents such as ethanol,

J t CH; Hs- --CN .HCI methylcellosolve, propylene glycol, etc. may beemployed. B CH8 7 Thereafter, working dilutions of the decreasingconcentra- CH CN-(BCH,- tions referred to above were made from eachstock solu- 1% 6 Q tion with inclusion of phosphate. butter to achievepH 3 3 o V 6-7. One ml. volumes of the varying working dilutions Amlxwle of g; of Y P were then transferred to sterile Petri dishes. Toeach dish" .yny i 10 gof Z-IIIEYCaPtWeQYIaH'ImC 7 containing the one ml.volume of a specific working diluhydl'ochlorldei 50 gof Powderedanhydrous Potasslum tion of a given compound were then added 9 ml. ofsterile carbQnate and 9 of ll-butfllml Was IeflllXed 2 penicillin seedagar and the test compound was thoroughly hours- The reactlon ImXturewas then cooled a filtered mixed into the agar. Solvent and buffercontrols were in- Th'e filtrate'was washed with aqueous 5% sodium carbold d Th t t o ani w r grown in brain heart nate h n wi h w and dried oanhydrous infusion broth for 18 hours at C. and diluted to m HesillmSulfate- The Solvent Was completely removed 35 concentration prior touse. The test organism's, in volunder reduced pressure. umes ofapproximately 0.8 1. were then mechanically T fr base s Converted to thehydrochloride y deposited on the cooled and hardened surface of the agardissolving the residue in either and addlflg 'Y Y P of each dish bymeans of an inocula replicator device. Chloride- Recfystallized from'aet11e-h10r0f0Im, t ;The dishes were then incubated for 18 hours at 35C. melted at 1381 0 C- 40 before being read. The minimal inhibitoryconcentra-' Al1alYSiS-Ca1Cd- 'fol' 2a 42 s 2 C, tion (MIC) valuerecorded for comparison was the least S, Found: amount of the-compoundunder test that completely in- 79 6.24. hibited the specific testorganism employed.

The product of Example 1 in the form of the desig- The results of theforegoing tests on the compound of nated acid-addition salt and severalother compounds inthe example and. on the other compounds included forcluded for purposes of comparison were tested to deter- 45 comparisonare given in the table below:

' TABLE Bacteriostatic Action Acid-Addition Salt Anesthetic Action B. S.Mycobact. Pszudo- S. BruceZZa Ncisseria L. Slactis subtillis aure usspp. monas E. coli paratyphi brtmchicatarrhalis casei R I aeruginosaseptica 1. Compound ofthe Example. T a 10 i 500 1,o00 1,000 500 25 50100 100 2; Cocaine Hydrochloride 3. 2,2-(2-hydroxypropylimino) bis[N-(2,6-dimethylphenyl)- N-methylacetamide1 .hydrov chloride Negativemine their respective local anesthetic and bacteriostatic action. Themethod of testingfor local anesthetic action comprised the simpleprocedure of placing .1 mg. of the compound of the tongue of a humanand'then noting subjectively the time it took for numbness to subside.To designate the degree of local anesthetic action of the compoundstested, an arbitrary scale was employed wherein was used to designateanesthetizing characteristics which persist for from 2-5 minutes. Onthis same scale l-+ would indicate anesthetic action for from 1520minutes, and for such action enduring from 1-2 hours. The designationwas used to indicate anesthetic action wherein numbness persisted for3-4 hours; the rating would be applied to coma marked degree. Theimportance of such characteristics will be more readily recognized whenit is noted that Compound 1 was found to be about 4 10 as effective asnovacaine or cocaine. In addition, Compound 1 showed significantbacteriostatic action. On the other hand, the results with respect toCompound 2 clearly demonstrated the unpredictability of combined localanesthetic and bacteriostatic action'upon variation of the amine residuefrom the definition thereof in accordance with the present invention. Itis of further significance in connection with the unpredictability offinding combined anesthetic and bacteriostatic action in a givencompound that, with repounds causing numbness for from 8-10 hours andthe spect to the local anesthetic novacaine, Moeller and 5 Schwarz, Ber.74B 1612 (1941) state that contrariwise the compound is a weak growthpromoter for bacteria.

EXAMPLE 2 Preparation of 2,2-(2-NIcrcapt0pr0pylimiiz0)Bis[N-(a,a-Dimethylphenethyl) -N-Methy!acemmide]Hydrochloride As in Example 1, amixture of 2-chloro-N-(a,a,-dimethylphenethyl)-N-methylacetarnide 58 g.,beta-aminopropylmercaptan hydrochloride 12.8 g., 50 g. of powderedanhydrous potassium carbonate, and 300 ml. of n-butanol is refluxed 24hours, cooled and filtered. The filtrate worked up as in Example 1yields the hydrochloride of the product formulated above.

EXAMPLE 3 Preparation of 2,2-(Z-Mercaptoethylimino)Bis[N-(a,a-Dimethylphenethyl) N Meflzylpropionamide]Hydrochloride CH CH3 OH;

wherein R is a divalent radical of the group consisting of ethylene,lower-alkyl substituted ethylene and hydroxy loWer-alkyl substitutedethylene, and X and Y are divalent radicals of the group consisting oflower alkylene and lower-alkyl substituted lower alkylene.

2. The compound, 2,2-(2-mercaptoethylimino)bis[N-(a,a-dirnethylphenethyl -N-methylacetamide] References Cited in the fileof this patent UNITED STATES PATENTS Seifter et a1 Feb. 5, 1957 FOREIGNPATENTS 1,060,404 Germany July 2, 1959 UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTION Patent No 3, l35 'l92 June 2 1964 William F,Bruce et a1,

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

for "either" read ether line 64 Column 3 line 38 read on column 6 line 2for "of" first occurrence for "dimethylphenyl" read dimethylphenethylSigned and sealed this 29th day of December 1964 (SEAL) Attest:

EDWARD J. BRENNER ERNEST W. SWIDER Attesting Officer Commissioner ofPatents

1. A COMPOUND OF THE GROUP CONSISTING OF ARALKYL AMINDE AND THENON-TOXIC ACID-ADDITION SALTS THEREOF, SAID AMIDES HAVING THE FORMULA